The purpose of this study was to investigate the protective effect of andrographolide in silica-induced pulmonary fibrosis (PF) in mice and its underlying mechanisms. Male Swiss albino mice were divided into five groups: Normal control group, disease control group (1.5 mg silica/60 μL/mice) via oropharyngeal route, low dose (LD) group received silica + andrographolide (3 mg/kg), high dose (HD) group received silica + andrographolide (10 mg/kg), andrographolide per se group received 10 mg/kg andrographolide. Various bronchoalveolar lavage fluid (BALF) and biochemical parameters, inflammatory cytokines, histology and protein expression studies were carried out. Andrographolide significantly reduced total protein concentration, albumin, accumulation of inflammatory cells and lactate dehydrogenase (LDH) level in BALF. We found that andrographolide intervention led to decreased levels of the inflammatory cells including neutrophils, macrophages and lymphocytes in the BALF of the treated animals. In addition, andrographolide significantly reduced nitrite (p < 0.01 at HD), malondialdehyde (p < 0.01 at HD) and upregulated glutathione (p < 0.01 at HD) in silica challenged animals. Andrographolide showed anti-fibrotic activity by reducing collagen deposition and inflammation in lung. Histopathology revealed that andrographolide decreased irregular cellular nodules, inflammatory infiltration and fibrosis. Andrographolide intervention significantly reduced the expression of N-cadherin, α-SMA and vimentin (mesenchymal markers) and upregulated the expression of E-cadherin (an epithelial marker). Hence, andrographolide elicits its anti-pulmonary fibrotic effect by halting the progression of epithelial-to-mesenchymal transition (EMT) via affecting fibroblasts. We, to the best of our knowledge prove for the first time that andrographolide possesses potent antifibrotic activity by targeting inflammatory cells and EMT associated fibroblasts.